Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus

ABSTRACT

Conventional spray-drying methods are improved by incorporation of a pressure nozzle and a diffuser plate to improve the flow of drying gas and a drying chamber extension to increase drying time, such improvements leading to the formation of homogeneous solid dispersions of drugs in concentration-enhancing polymers.

BACKGROUND OF THE INVENTION

The use of spray-drying to produce powders from fluid feed stocks iswell known, with applications ranging from powdered milk to bulkchemicals and pharmaceuticals. See U.S. Pat. No. 4,187,617 and Mujumbaret al., Drying 91, pages 56-73 (1991). The use of spray-drying to formsolid amorphous dispersions of drugs and concentration-enhancingpolymers is also known. See commonly owned European Patent ApplicationsNos. 0 901 786, 1 027 886, 1 027 887, 1 027 888, and commonly-owned PCTApplications Nos: WO 00/168092 and WO 00/168055. And the use of aperforated plate as an air disperser for a spray-dryer using a nozzleatomizer is also known. See Masters, Spray Drying Handbook, pages263-268(4^(th) ed 1985).

A typical spray-drying apparatus comprises a drying chamber, atomizingmeans for atomizing a solvent-containing feed into the drying chamber, asource of heated drying gas that flows into the drying chamber to removesolvent from the atomized solvent-containing feed and product collectionmeans located downstream of the drying chamber. Examples of suchapparatus include Niro Models PSD-1, PSD-2 and PSD-4 (Niro A/S, Soeborg,Denmark). When used for forming solid amorphous dispersions byspray-drying, conventional wisdom suggests that to achieve rapid removalof solvent required to form a homogeneous solid amorphous dispersion,the droplets of atomized solvent-containing feed should be small. Theprior art therefore uses spray-drying apparatus equipped with atwo-fluid nozzle for atomizing the solvent-containing feed. Such nozzlesproduce small droplets of feed solution, typically 5 to 30 μm indiameter, and turbulent mixing of the liquid feed droplets and dryinggas, leading to rapid drying of the fluid to form solid particles. Whenused in the prescribed manner, such spray-drying apparatus are effectivein forming substantially amorphous and substantially homogeneoussolid-amorphous dispersions of drug and polymer that show concentrationenhancement when introduced to an environment of use. However, as notedabove, the spray-dried particles produced in such apparatus often havesmall median particle sizes (less than about 30 μm in diameter) and alarge amount of “fines” (particles with diameters of less than about 10μm). The product also typically has a high specific volume. Specificvolume is the volume of the spray-dried powder divided by itsmass—typically reported in units of cm³/g. Generally, the higher thespecific volume of a powder, the poorer its flow characteristics. As aresult, the dispersions produced using a spray-drying apparatus equippedwith a two-fluid nozzle have relatively poor flow characteristics andpoor collection efficiency.

The inventors have found that the flow characteristics and collectionefficiency of spray-dried dispersions can be improved by using aspray-drying apparatus equipped with atomizing means that producesdroplets with an average droplet diameter of 50 μm or larger, with lessthan about 10 vol % of the droplets having a size less than 10 μm. Suchan atomizing means is referred to herein as a “pressure nozzle.” It hasbeen discovered that homogeneous solid amorphous dispersions formedusing pressure nozzles have relatively larger median particle sizes,with minimal fines present. The resulting dispersions therefore haveimproved flow characteristics and improved collection efficiencies. Seecommonly owned U.S. Provisional Application No. 60/353,986 (AttorneyDocket PC23203) filed Feb. 1, 2002 and incorporated herein by reference.

However, all else being equal, the rate of removal of solvent from suchlarger droplets produced by a pressure nozzle is slower than that fromsmaller droplets, such as those produced by a two-fluid nozzle.Conventionally, to counteract this tendency for large droplets to drymore slowly, drying gas is introduced in a flow direction that is notparallel to the atomized droplet flow. Drying gas introduced in thismanner induces large circulation cells that carry droplets or particlesinitially directed downward back up to the top of the dryer. Such flowcauses turbulent mixing of the drying gas and atomized spray solution,leading to more rapid drying of the droplets. However, theseconventional methods for spray-drying large particles result in (1)build-up of material on the nozzle itself, as well as on the dryersurface near the drying gas inlet, (2) excessively rapid drying of someof the particles, and (3) less uniform drying conditions. As a result,the product produced tends to have poor content uniformity, highspecific volumes, poor flow characteristics, and when the build-upoccurs on hot surfaces, the potential for chemical degradation of theproduct. Thus, such non-parallel introduction of drying gas to aconventional spray-drying apparatus should be avoided.

There is therefore a need in the art for an improved spray-dryingprocess that results in the production of solid amorphous dispersions athigh yield with improved flow characteristics, improved contentuniformity, and improved collection efficiency.

BRIEF SUMMARY OF THE INVENTION

According to the present invention there is provided an improved methodfor making homogeneous spray-dried solid amorphous dispersions ofpharmaceuticals in a concentration enhancing polymer, the improvedmethod including the use of a gas-dispersing means that facilitatesorganized plug flow of the drying gas, a drying chamber having aparticular height and volume and an atomizing means that producesdroplets with a median droplet diameter of 50 μm or larger, with lessthan about 10 vol % of the droplets having a size less than 10 μm,referred to herein as a pressure nozzle.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a cross-sectional schematic of a spray-drying apparatusequipped with a conventional non-parallel introduction of drying gas topromote rapid mixing of the drying gas and atomized solvent-containingfeed.

FIG. 2 is a cross-sectional schematic of a portion of the apparatusshown in FIG. 1 depicting product build-up around the atomizer.

FIG. 3 is a schematic of a typical two-fluid spray nozzle.

FIG. 4 is a cross-sectional schematic of the apparatus shown in FIG. 1with a gas-dispersing means to provide organized plug flow of the dryinggas.

FIG. 5 is a cross-sectional schematic of the apparatus shown in FIG. 1with both a gas-dispersing means and an extension of the drying chamber.

FIGS. 6-7 are graphs showing a comparison of median particle sizes andparticle size distributions of spray-dried drug dispersions made using aconventional spray-drying apparatus and using an apparatus of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

Turning to the drawings, wherein the same numerals refer to likeelements, there is shown in FIG. 1 a typical prior art spray-dryingapparatus 10. In the following discussion it is assumed that thespray-drying apparatus is cylindrical. However, the dryer may take anyother shape suitable for spray drying a solvent-bearing feed, includingsquare, rectangular, and octagonal. The spray-drying apparatus is alsodepicted as having one atomizing means. However, multiple atomizingmeans can be included in the spray-drying apparatus to achieve higherthroughput of the solvent-bearing feed.

The apparatus shown in FIG. 1 comprises a drying chamber 20, a dryingchamber top 21, a collection cone 22, connecting duct 26 connected tothe distal end 23 of the collection cone, a cyclone 28 and a collectionvessel 29. An atomizer 30 is shown atomizing a solvent-bearing feed 32.Drying gas from a drying gas source (not shown) is introduced throughdrying gas inlets 31, typically via an annular opening in drying chambertop 21, in a flow direction that is not parallel to the atomized dropletflow which is typically introduced vertically at the center of the topof the dryer via atomizing means 30. The non-parallel drying gas flowtypically has an inward vector that is toward the atomized droplets nearthe center of the chamber and a radial vector that is an off-centerflow. Drying gas introduced in this manner induces large scale flow thatis circular (generally parallel to the circumference of the cylindricalchamber), and that creates large circulation cells that carry dropletsor particles initially downward and then back up to the drying chambertop 21 so as to cause a large fraction to pass near drying gas inlet 31and atomizing means 30, as indicated by the arrows in FIG. 1. Such flowintroduces rapid and turbulent mixing of the drying gas and atomizedsolvent-bearing feed 32, leading to rapid drying of the droplets to formthe solid particles of the dispersion. The solid dispersion particlesare entrained by the drying gas through collection cone 22 to connectingduct 26, and then to cyclone 28. In the cyclone, the particles areseparated from the drying gas and evaporated solvent, allowing theparticles to be collected in collection vessel 29. Instead of a cyclone,a filter can be used to separate and collect the particles from thedrying gas and evaporated solvent.

The drying gas may be virtually any gas, but to minimize the risk offire or explosions due to ignition of flammable vapors, and to minimizeundesirable oxidation of the drug, concentration-enhancing polymer, orother materials in the dispersion, an inert gas such as nitrogen,nitrogen-enriched air, or argon is utilized. The temperature of thedrying gas at the gas inlet of apparatus 10 is typically from about 60°to about 300° C. The temperature of the product particles, drying gas,and evaporated solvent at the outlet or distal end 23 of collection cone22 typically ranges from about 0° C. to about 100° C.

As noted above, conventional wisdom is that the formation of ahomogeneous solid amorphous dispersion of a low-solubility drug and aconcentration-enhancing polymer requires rapid solidification of theatomized droplets. To accomplish this, the prior art has used anapparatus such as that shown in FIG. 1 equipped with atomizing meanssuch as the two-fluid nozzle shown in FIG. 3, that produces relativelysmall droplets, generally with median diameters of 50 μm or less, andtypical average droplet diameters of 5 to 30 μm. In such two-fluidnozzles, the solvent-containing feed 32 is mixed with an atomizing gas36, such as air or nitrogen, atomizing the feed into small droplets.This small droplet size, along with the turbulent mixing of a portion ofthe drying gas within the nozzle as well as at the outlet of the nozzle,results in a large surface area and driving force for evaporation of thesolvent from the droplet, leading to rapid removal of solvent from thedroplet. The resulting dispersion particles typically have mediandiameters of 30 μm or less. In addition, a large proportion, typicallygreater than about 10 vol % of the particles, constitute fines havingdiameters of less than 10 μm, which leads to relatively poor flowcharacteristics for the dispersion particles. These fines not onlygenerally lead to poor flow characteristics for the product, but aresufficiently small that the static electrical charge they often incur islarge relative to their mass due to their large surface-to-mass ratio.As a result, they have poor collection efficiencies in cyclone-based andfilter-based collections schemes.

The inventors have discovered that spray-dried dispersions with improvedproperties can be obtained by using a pressure nozzle, that is,atomizing means that produces droplets with a median droplet diameter of50 μm or larger, with less than about 10 vol % of the droplets having asize less than 10 μm. The droplets produced by such atomizing means aresignificantly larger than those used in conventional spray-dryingapparatus, such as those equipped with a two-fluid nozzle. As a result,the rate of removal of solvent from such larger droplets is slower thanthat from smaller droplets. Despite this slower rate of solvent removal,the inventors have discovered that homogeneous spray-dried dispersionscan be formed using such atomizing means.

When a pressure nozzle is used in a conventional spray-dryer, apparatussuch as that shown in FIG. 1, the resulting non-parallel flow createslarge circulation cells as described above that causes rapid andturbulent mixing of the drying gas and atomized spray solution, leadingto rapid drying of the larger droplets. This approach has the benefit ofallowing the larger droplets formed by pressure nozzles to be dried in aconventional-sized drying chamber. As a result, homogeneous solidamorphous dispersions may be successfully made in this manner. However,the resulting rapid drying of the particles nevertheless can lead tohigh specific volume product with relatively poor flow characteristics.In addition, the drying conditions for the droplets are not uniform,resulting in a product that has a wide range of particle sizes,densities, and morphologies. Finally, as explained below, in such anapparatus there is a build-up of material therein that reduces yield andcan lead to frequent shutdowns of the apparatus.

A principal drawback of the prior art apparatus of FIG. 1, especiallywhen equipped with a pressure nozzle atomizer, is the build-up ofmaterial 34 on the inside of drying chamber top 21 near the drying gasinlets 31 and on and around spray nozzle 30. This build-up of material34 is believed to be due in part to the circulation cells that carrydroplets or partially dried particles up to chamber top 21 and pastdrying gas inlet 31 and atomizing means 30 as noted above and asillustrated by the arrows in FIG. 1. This causes droplets of thesolvent-bearing feed 32 as well as partially dried particles to contactthe hot surfaces of drying chamber top 21 and atomizing means 30 beforethey are fully dry. The accumulation of material 34 on and around theatomizer 30 depicted in FIG. 2 eventually impedes the flow ofsolvent-bearing feed 32, which in turn adversely alters the atomizationof the feed, resulting in changes in droplet size and diminishing theflow of feed, thereby reducing the capacity of the spray-dryingapparatus. This requires frequent shutdown and cleaning of the apparatusto maintain high product quality and productivity.

The inventors have made the surprising discovery that by introducing thedrying gas so that its primary axis of flow is generally parallel to theaxis of atomizing means 30 and so that it flows relatively uniformlyacross the diameter of drying chamber 20, even though flow within thedrying chamber is locally turbulent, a generally downward “organizedplug flow” (described below) may be maintained for a significantdistance away from chamber top 21. Introducing the drying gas in thismanner (1) prevents circulation of particles upwardly back up to chambertop 21; (2) avoids build-up material 34 on atomizing means 30, chambertop 21, and drying gas inlets 31; (3) provides more uniform dryingconditions for the droplets, leading to more uniform product; and (4)allows slower drying of the droplets, which generally allows for adenser, lower specific volume product to be formed that has improvedflow characteristics.

There is shown in FIG. 4 a cross-sectional schematic of a modifiedspray-drying apparatus 11 without any product collection means, whichincludes gas-dispersing means 24 situated within drying chamber 20 andbelow drying chamber top 21. Gas-dispersing means 24 allows drying gasto be introduced into chamber 20 so that it is initially generallyparallel to the axis of atomizing means 30 and is distributed relativelyevenly across the diameter of the apparatus, shown schematically by themultiple downwardly pointing arrows in the upper portion of FIG. 4. Thedrying gas is thus introduced so that its flow through the upper portionof the spray-dryer can be described as “organized plug flow” away fromthe top of the apparatus. By “organized plug flow” is meant that theflow of drying gas satisfies at least one of the following twoconditions. First, the drying gas velocity vector parallel to the wallsof drying chamber 20, at any point across the diameter of the dryingchamber, is predominantly, towards the distal end 23 of collection cone22. Second, any circulation cells near the top of the drying chamber aresmall, with the diameter of the circulation cells being less than 20% ofthe diameter of, the drying chamber, the circulation cells being locatedat least 20 cm below gas-dispersing means 24. This organized plug flowaway from the top of the dryer may extend essentially to the distal endof the dryer or may extend only a portion of the way down the length ofthe dryer. It is generally only necessary for the downward organizedplug flow to extend sufficiently far down the dryer (at least about 20cm) such that few, if any, droplets or particles may circulate from thelower portion of the dryer back to the top of the dryer in the vicinityof gas-dispersing means 24 and atomizing means 30. Thus, organized plugflow of drying gas dramatically decreases the formation of circulationcells that entrain droplets or particles back up to the top of thedrying chamber.

Two additional benefits of organized plug flow are

(1) the velocity of drying gas is uniform across the entire diameter ofthe drying chamber, resulting in a more uniform residence time ofparticles in the drying chamber and improved uniformity of particlesize, density and morphology, and(2) the particles generally dry more slowly, thus allowing denser, lowerspecific volume particles to be formed. Such low specific volumeproducts are generally preferred as they have improved flowcharacteristics.

FIG. 4 illustrates one way for accomplishing the introduction of dryinggas in the manner described above and that has been shown to achieve thedesired organized plug flow down a portion of the drying chamber. In oneembodiment, gas-dispersing means 24 consists of a plate coextensive withthe interior of drying chamber 20 and bearing a multiplicity of evenlydistributed perforations occupying from about 0.5 to about 5% of thesurface area of the plate, preferably about 1%, with each perforationbeing from about 0.1 to about 6 mm in diameter, preferably from about1.0 to about 3.0 mm. In another embodiment, the density of perforationsis lower in the center of the diffuser plate, where the atomizing meansextends through the plate into the drying chamber. For a cylindricaldrying chamber, this lower density region extends from the center of thediffuser plate to a diameter that is about 10% to about 35% of thediameter of the drying chamber. The density of perforations in this lowdensity region is about 10% to about 50% the density of perforations inthe outer part of the diffuser plate. Gas-dispersing means 24 creates anorganized plug flow of drying gas, (depicted by the downward arrows inFIG. 4) and dramatically decreases large circulation cells that carrydroplets and particles to the gas-dispersing means 24 and atomizingmeans 30. This generally greatly reduces product build-up in those twoareas.

However, the spray-dryer apparatus shown in FIG. 4 generally limits thesize of droplets and, in turn, product particles that may be formedwithout excessive build-up of material 34 on the walls of the lowerportion of the drying chamber 20 and collection cone 22. One approach toavoid this problem is to adjust the atomizing conditions to producesmaller droplets and particles. A second approach is to increase thedrying gas inlet temperature (and, in turn, the outlet temperature),thus inducing more rapid droplet drying. Both of these approaches,although successful, are not preferred as they lead to smaller particlesizes and/or higher particle specific volumes, both of which result in aproduct with poor flow characteristics. However, the inventors havefound that by increasing the height of the drying chamber, i.e., theminimum distance to any surface of collection cone 22, that product canbe obtained having (1) increased product yield (due to little or nobuild-up of material on the inner surfaces of the drying chamber or thecollection cone), (2) increased particle size and (3) reduced specificvolume.

There is shown in FIG. 5 a cross-sectional schematic of a modifiedspray-drying apparatus 13 of the present invention that includesgas-dispersing means 24 of the same design as described in connectionwith FIG. 4. Apparatus 13 also has a drying chamber 20 having a height Hthat is larger than that of a conventional drying chamber. The largerheight results in an increased minimum distance that a droplet travelsbefore impinging on the walls of drying chamber 20 or of collection cone22, allowing the droplet to dry sufficiently so that there is minimalbuild-up of material 34 on the inner surfaces of the drying chamber orcollection cone. The larger height also allows for selection ofprocessing conditions that result in improved properties of the productdispersion. For example, a larger height allows for longer drying times,allowing the use of atomizing means that produces larger droplets. As aresult, a product dispersion with larger particles and thereforeimproved flow characteristics and collection efficiencies can beproduced. The larger height also allows for selection of processconditions that lead to slower drying of the droplets, resulting in aproduct with a lower specific volume and thus improved flowcharacteristics. Use of the modified apparatus 13 equipped withatomizing means 30 that produces droplets with an average dropletdiameter of 50 μm or larger and with less than about 10 vol % of thedroplets having a size less than 10 μm, gas-dispersing means 24 thatresults in organized plug flow of the drying gas, and a larger height Hthat results in an increased minimum distance the droplets travel beforeimpinging on the walls of drying chamber 20 or of collection cone 22,results in the formation of a homogeneous solid amorphous dispersion athigh yield having large particle sizes, minimal fines, low specificvolumes, high collection efficiencies, and good flow characteristics,with minimal build-up of material 34 on atomizing means 30, chamber lid21, drying gas inlets 31, drying chamber 20 or collection cone 22.

The height H of the drying chamber 20 that provides a sufficient minimumdistance the droplets travel before impinging on the walls of dryingchamber 20 or of collection cone 22 is a function of several factors,including (1) the drying characteristics of the solvent-bearing feed,(2) the flow rates of solvent-bearing feed and drying gas to thespray-dryer, (3) the inlet temperature of the drying gas, (4) thedroplet size and droplet size distribution and (5) the average residencetime of material in the spray-dryer.

The inventors have found that even a small increase in the height of thedrying chamber can result in improved performance of a spray-dryer. Forexample, a conventional Niro PSD-1 spray-drying apparatus designed foruse with a solvent-bearing feed has a height of about 0.8 m. When apressure nozzle is used with such a dryer, a significant fraction of thedroplets are not sufficiently dry before they impinge on the wall of thedrying chamber and the collection cone, resulting in build-up ofmaterial in the dryer and poor yields and poor content uniformity.However, a 1.25-fold increase in height to 1.0 m allows the droplets tobecome sufficiently dry so that build-up of material on the interiordryer surfaces is minimized.

The inventors have also shown that a 3.25-fold increase in the height ofa conventional Niro PSD-1 spray-dryer (to 2.6 m) allows for even greaterflexibility in producing homogeneous solid amorphous spray-drieddispersions with desirable properties. With such an arrangement, thespray-drying conditions can be selected that allow for formation ofdispersions with large particles (i.e., greater than 50 μm), lowspecific volumes (i.e., less than 4 mL/gm) at high yield (i.e., greaterthan 95%). Dispersions with such properties cannot be produced on aconventional PSD-1 spray-dryer.

Through experimentation and finite-element modeling of the spray-dryingprocess, the inventors have determined that for production of ahomogeneous solid amorphous dispersion of a given drug and a givenconcentration-enhancing polymer, the height of the drying chamber shouldbe at least 1.0 m to allow sufficient minimum distance for a droplet totravel before impinging on a surface of the drying apparatus. Morepreferably, the height of the drying chamber is at least 1.5 m, and mostpreferably at least 2.0 m. Spray-dryers that meet these minimum heightrequirements, combined with a gas-means that results in organized plugflow of the drying, gas and a pressure nozzle, will result in theproduction of high-quality product at high yield.

While the height of the drying chamber is critical to determining theminimum distance a droplet travels before impinging on a surface of thedrying apparatus, the volume of the drying apparatus is also important.The capacity of a spray-dryer is determined, in part, by matching theflow rate of the solvent-bearing feed to the temperature and flow of thedrying gas. Simply stated, the temperature and flow rate of the dryinggas must be sufficiently high so that sufficient heat for evaporatingthe solvent-bearing feed is delivered to the spray-drying apparatus.Thus, as the flow rate of solvent-bearing feed is increased, the flowrate and/or temperature of the drying gas must be increased to providesufficient energy for formation of the desired product. Since theallowable temperature of the drying gas is often limited by the chemicalstability of the drug present in the solvent-bearing feed, the dryinggas flow rate is often increased to allow for an increased capacity(i.e., increased flow of solvent-bearing feed) of the spray-dryingapparatus. For a drying apparatus with a given volume, an increase inthe drying gas flow rate will result in a decrease in the averageresidence time of droplets or particles in the dryer, which could leadto insufficient time for evaporation of solvent from the droplets toform a solid particle prior to impinging on a surface in thespray-dryer, even though the drying chamber has a greater height than aconventional dryer. As a result, the volume of the dryer must besufficiently large that the droplet is sufficiently dry by the time itimpinges on internal surfaces of the dryer to prevent build-up ofmaterial.

One may take into account this drying time by the “average residencetime” τ, defined as the ratio of the volume of the spray-dryingapparatus to the volumetric flow rate of drying gas fed to the dryingapparatus, or

${\tau = \frac{V_{dryer}}{G}},$

where V_(dryer) is the volume of the spray dryer and G is the volumetricflow rate of drying gas fed to the dryer. The volume of the dryer is thesum of the volumes of drying chamber 20 and collection cone 22. For acylindrical spray-drying apparatus with a diameter D, a height H of thedrying chamber, and a height L of the collection cone, the volume of thedryer V_(dryer) is given as

$V_{dryer} = {{\frac{\pi}{4}D^{2}H} + {\frac{\pi}{12}D^{2}L}}$

The inventors have determined that the average residence time should beat least 10 seconds to ensure that the droplets have sufficient time todry prior to impinging on a surface within the spray-dryer; morepreferably, the average residence time is at least 15 seconds and mostpreferably at least 20 seconds.

For example, for a volumetric flow of drying gas of 0.25 m³/sec and anaverage residence time of 20 seconds, the required volume of thespray-drying apparatus can be calculated as follows:

V _(dryer) =τ·G=20 sec·0.25 m³/sec=5 m³.

Thus, for a spray-dryer with a volume of 5 m³, a height H of 2.3 m and acollection cone 22 with a cone angle 27 of 60° (meaning that the heightL of the collection cone 22 is equal to the diameter D of the dryingchamber 20 or L=D), the required diameter D of the spray-drying chambercan be calculated from the above equation, as follows:

$\begin{matrix}{V_{dryer} = {{\frac{\pi}{4}D^{2}H} + {\frac{\pi}{12}D^{2}L}}} \\{= {{\frac{\pi}{4}D^{2}H} + {\frac{\pi}{12}D^{3}}}} \\{= 5} \\{{= {{\frac{\pi}{4}D^{2}2.3} + {\frac{\pi}{12}D^{3}}}},}\end{matrix}$ or D = 1.5  m.

Provided the diameter of the spray-dryer is at least 1.5 m, the averageresidence time, of particles in the dryer will be at least 20 seconds,and the droplets produced by the pressure nozzle will be sufficientlydry by the time they impinge on the surface of the dryer to minimizebuild-up of material on the walls of the drying chamber and collectioncone.

Using these criteria, the height and volume of a spray-dryer necessaryto form a homogeneous solid amorphous dispersion of a drug andconcentration enhancing polymer at high yield and with the desiredproperties can be determined.

The Drug

The present invention is useful in the formation of solid amorphousdispersions of a drug and a concentration-enhancing polymer. The term“drug” is conventional, denoting a compound having beneficialprophylactic and/or therapeutic properties when administered to ananimal, especially humans. The drug does not need to be a low-solubilitydrug in order to benefit from this invention, although low-solubilitydrugs represent a preferred class for use with the invention. Even adrug that nonetheless exhibits appreciable solubility in the desiredenvironment of use can benefit from the increasedsolubility/bioavailability made possible by this invention if theaddition of the concentration-enhancing polymer can reduce the size ofthe dose needed for therapeutic efficacy or increase the rate of drugabsorption in cases where a rapid onset of the drug's effectiveness isdesired.

The present invention is particularly suitable for preparing a soliddispersion of and enhancing the solubility of a “low-solubility drug,”meaning that the drug may be either “substantially water-insoluble,”which means that the drug has a minimum aqueous solubility atphysiologically relevant pH (e.g., pH 1-8) of less than 0.01 mg/mL,“sparingly water-soluble,” that is, has an aqueous solubility up toabout 1 to 2 mg/mL, or even low to moderate aqueous-solubility, havingan aqueous-solubility from about 1 mg/mL to as high as about 20 to 0.40mg/mL. The invention finds greater utility as the solubility of the drugdecreases. Thus, compositions of the present invention are preferred forlow-solubility drugs having a solubility of less than 10 mg/mL, morepreferred for low-solubility drugs having a solubility of less than 1mg/mL, and even more preferred for low-solubility drugs having asolubility of less than 0.1 mg/mL. In general, it may be said that thedrug has a dose-to-aqueous solubility ratio greater than 10 mL, and moretypically greater than 100 mL, where the drug solubility (mg/mL) is theminimum value observed in any physiologically relevant aqueous solution(e.g., those with pH values between 1 and 8) including USP simulatedgastric and intestinal buffers, and the dose is in mg. Thus, adose-to-aqueous-solubility ratio may be calculated by dividing the dose(in mg) by the solubility (in mg/mL).

Preferred classes of drugs include, but are not limited to,antihypertensives, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,antiinflammatories, antipsychotic agents, cognitive enhancers,antiatherosclerotic agents, cholesterol-reducing agents, antiobesityagents, autoimmune disorder agents, anti-impotence agents, antibacterialand antifungal agents, hypnotic agents, anti-Parkinsonism agents,anti-Alzheimer's disease agents, antibiotics, anti-depressants,antiviral agents, glycogen phosphorylase inhibitors, and cholesterolester transfer protein (CETP) inhibitors.

Each named drug should be understood to include the neutral form of thedrug, pharmaceutically acceptable salts, as well as prodrugs. Specificexamples of antihypertensives include prazosin, nifedipine, amlodipinebesylate, trimazosin and doxazosin; specific examples of a bloodglucose-lowering agent are glipizide and chlorpropamide; a specificexample of an anti-impotence agent is sildenafil and sildenafil citrate;specific examples of antineoplastics include chlorambucil, lomustine andechinomycin; a specific example of an imidazole-type antineoplastic istubulazole; a specific example of an anti-hypercholesterolemic isatorvastatin calcium; specific examples of anxiolytics includehydroxyzine hydrochloride and doxepin hydrochloride; specific examplesof anti-inflammatory agents include betamethasone, prednisolone,aspirin, piroxicam, valdecoxib, carprofen, celecoxib, flurbiprofen and(+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea;a specific example of a barbiturate is phenobarbital; specific examplesof antivirals include acyclovir, nelfinavir, and virazole; specificexamples of vitamins/nutritional agents include retinol and vitamin E;specific examples of beta blockers include timolol and nadolol; aspecific example of an emetic is apomorphine; specific examples of adiuretic include chlorthalidone and spironolactone; a specific exampleof an anticoagulant is dicumarol; specific examples of cardiotonicsinclude digoxin and digitoxin; specific examples of androgens include17-methyltestosterone and testosterone; a specific example of a mineralcorticoid is desoxycorticosterone; a specific example of a steroidalhypnotic/anesthetic is alfaxalone; specific examples of anabolic agentsinclude fluoxymesterone and methanstenolone; specific examples ofantidepression agents include sulpiride,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine,3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine,pyroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; specificexamples of antibiotics include carbenicillin indanylsodium,bacampicillin hydrochloride, troleandomycin, doxycyline hyclate,ampicillin and penicillin G; specific examples of anti-infectivesinclude benzalkonium chloride and chlorhexidine; specific examples ofcoronary vasodilators include nitroglycerin and mioflazine; a specificexample of a hypnotic is etomidate; specific examples of carbonicanhydrase inhibitors include acetazolamide and chlorzolamide; specificexamples of antifungals include econazole, terconazole, fluconazole,voriconazole, and griseofulvin; a specific example of an antiprotozoalis metronidazole; specific examples of anthelmintic agents includethiabendazole and oxfendazole and morantel; specific examples ofantihistamines include astemizole, levocabastine, cetirizine,decarboethoxyloratadine, and cinnarizine; specific examples ofantipsychotics include ziprasidone, olanzepine, thiothixenehydrochloride, fluspirilene, risperidone and penfluridole; specificexamples of gastrointestinal agents include loperamide and cisapride;specific examples of serotonin antagonists include ketanserin andmianserin; a specific example of an anesthetic is lidocaine; a specificexample of a hypoglycemic agent is acetohexamide; a specific example ofan anti-emetic is dimenhydrinate; a specific example of an antibacterialis cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA;specific examples of anti-Alzheimer's Disease agents are THA anddonepezil; a specific example of an anti-ulcer agent/H2 antagonist isfamotidine; specific examples of sedative/hypnotic agents includechlordiazepoxide and triazolam; a specific example of a vasodilator isalprostadil; a specific example of a platelet inhibitor is prostacyclin;specific examples of ACE inhibitor/antihypertensive agents includeenalaprilic acid, quinapril and lisinopril; specific examples oftetracycline antibiotics include oxytetracycline and minocycline;specific examples of macrolide antibiotics include erythromycin,clarithromycin, and spiramycin; a specific example of an azalideantibiotic is azithromycin; specific examples of glycogen phosphorylaseinhibitors include[R-(R*S*)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamideand 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide;specific examples of cholesterol ester transfer protein inhibitorsinclude[2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester,[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester and[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

Solid Drug-Containing Dispersion

The spray-dried product formed by the method of the present inventioncomprise dispersions of a drug and at least one concentration-enhancingpolymer. At least a major portion of the drug in the dispersion isamorphous. As used herein, the term “a major portion” of the drug meansthat at least 60% of the drug in the dispersion is in the amorphousform, rather than the crystalline form. By “amorphous” is meant simplythat the drug is in a non-crystalline state. Preferably, the drug in thedispersion is substantially amorphous. As used herein, “substantiallyamorphous” means that the amount of the drug in crystalline form doesnot exceed about 25%. More preferably, the drug in the dispersion is“almost completely amorphous” meaning that the amount of drug in thecrystalline form does not exceed about 10%. Amounts of crystalline drugmay be measured by Powder X-Ray Diffraction (PXRD), Scanning ElectronMicroscope (SEM) analysis, differential scanning calorimetry (DSC), orany other standard quantitative measurement.

The composition formed by the inventive method may contain from about 1to about 80 wt % drug, depending on the dose of the drug and theeffectiveness of the concentration-enhancing polymer. Enhancement ofaqueous drug concentrations and relative bioavailability are typicallybest at low drug levels, typically less than about 25 to about 40 wt %.However, due to the practical limit of the dosage form size, higher druglevels are often preferred and in many cases perform well.

The amorphous drug can exist within the solid amorphous dispersion as apure phase, as a solid solution of drug homogeneously distributedthroughout the polymer or any combination of these states or thosestates that lie intermediate between them. The dispersion is preferablysubstantially homogeneous so that the amorphous drug is dispersed ashomogeneously as possible throughout the polymer. As used herein,“substantially homogeneous” means that the fraction of drug that ispresent in relatively pure amorphous domains within the solid dispersionis relatively small, on the order of less than 20%, and preferably lessthan 10% of the total amount of drug.

While the dispersion formed by the inventive method may have somedrug-rich domains, it is preferred that the dispersion itself have asingle glass transition temperature (T_(g)), which confirms that thedispersion is substantially homogeneous. This is in contrast to a simplephysical mixture of pure amorphous drug particles and pure amorphouspolymer particles which generally display two distinct T_(g)s, one beingthat of the drug and one that of the polymer. T_(g) as used herein isthe characteristic temperature where a glassy material, upon gradualheating, undergoes a relatively rapid (e.g., in 10 to 100 seconds)physical change from a glassy state to a rubbery state. The T_(g) of anamorphous material such as a polymer, drug or dispersion can be measuredby several techniques, including by a dynamic mechanical analyzer (DMA),a dilatometer, a dielectric analyzer, and by DSC. The exact valuesmeasured by each technique can vary somewhat, but usually fall within10° to 30° C. of each other. Regardless of the technique used, when anamorphous dispersion exhibits a single T_(g), this indicates that thedispersion is substantially homogenous. Dispersions formed by the methodof the present invention that are substantially homogeneous generallyare more physically stable and have improved concentration-enhancingproperties and, in turn, improved bioavailability, relative tononhomogeneous dispersions.

Concentration-Enhancing Polymers

Concentration-enhancing polymers suitable for use in the compositionsformed by the inventive method should be inert, in the sense that theydo not chemically react with the drug in an adverse manner. The polymercan be neutral or ionizable, and should have an aqueous solubility of atleast 0.1 mg/mL over at least a portion of the pH range of 1-8.

The polymer is a “concentration-enhancing polymer,” meaning that itmeets at least one, and preferably both, of the following conditions.The first condition is that the concentration-enhancing polymerincreases the maximum drug concentration (MDC) of the drug in theenvironment of use relative to a control composition consisting of anequivalent amount of the undispersed drug but no concentration-enhancingpolymer. That is, once the composition is introduced into an environmentof use, the polymer increases the aqueous concentration of drug relativeto the control composition. Preferably, the polymer increases the MDC ofthe drug in aqueous solution by at least 1.25-fold relative to a controlcomposition, more preferably by at least 2-fold, and most preferably byat least 3-fold. The second condition is that theconcentration-enhancing polymer increases the area under theconcentration versus time curve (AUC) of the drug in the environment ofuse relative to a control composition consisting of the drug but nopolymer. (The calculation of an AUC is a well-known procedure in thepharmaceutical arts and is described, for example, in Welling,“Pharmacokinetics Processes and Mathematics,” ACS Monograph 185 (1986).)More specifically, in the environment of use, the composition comprisingthe drug and the concentration-enhancing polymer provides an AUC for anyperiod of from about 90 to about 270 minutes following introduction tothe use environment that is at least 1.25-fold that of a controlcomposition consisting of an equivalent quantity of drug but no polymer.Preferably, the AUC provided by the composition is at least 2-fold, morepreferably at least 3-fold that of the control composition.

As used herein, a “use environment” can be either the in vivoenvironment of the GI tract of a mammal, particularly a human, or the invitro environment of a test solution, such as phosphate buffered saline(PBS) solution or Model Fasted Duodenal (MFD) solution.

Concentration-enhancing polymers suitable for use with the presentinvention may be cellulosic or non-cellulosic. The polymers may beneutral or ionizable in aqueous solution. Of these, ionizable andcellulosic polymers are preferred, with ionizable cellulosic polymersbeing more preferred.

It is preferred that the concentration-enhancing polymer be“amphiphilic” in nature, meaning that the polymer has hydrophobic andhydrophilic portions. Amphiphilic polymers are preferred because it isbelieved that such polymers tend to have relatively strong interactionswith the drug and may promote the formation of various types ofpolymer/drug assemblies in solution. A particularly preferred class ofamphiphilic polymers are those that are ionizable, the ionizableportions of such polymers, when ionized, constituting at least a portionof the hydrophilic portions of the polymer. For example, while notwishing to be bound by a particular theory, such polymer/drug assembliesmay comprise hydrophobic drug clusters surrounded by theconcentration-enhancing polymer with the polymer's hydrophobic regionsturned inward towards the drug and the hydrophilic regions of thepolymer turned outward toward the aqueous environment. Alternatively,depending on the specific chemical nature of the drug, the ionizedfunctional groups of the polymer may associate, for example, viaion-pairing or hydrogen bonds, with ionic or polar groups of the drug.In the case of ionizable polymers, the hydrophilic regions of thepolymer would include the ionized functional groups. In addition, therepulsion of the like charges of the ionized groups of such polymers(where the polymer is ionizable) may serve to limit the size of thepolymer/drug assemblies to the nanometer or submicron scale. Suchdrug/concentration-enhancing polymer assemblies in solution may wellresemble charged polymeric micellar-like structures. In any case,regardless of the mechanism of action, the inventors have observed thatsuch amphiphilic polymers, particularly ionizable cellulosic polymerssuch as those listed below, have been shown to interact with drug so asto maintain a higher concentration of drug in an aqueous useenvironment.

One class of polymers suitable for use with the present inventioncomprises non-ionizable (neutral) non-cellulosic polymers. Exemplarypolymers include: vinyl polymers and copolymers having at least onesubstituent selected from the group consisting of hydroxyl,alkylacyloxy, and cyclicamido; polyvinyl alcohols that have at least aportion of their repeat units in the unhydrolyzed (vinyl acetate) form;polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone;polyethylene polyvinyl alcohol copolymers, andpolyoxyethylene-polyoxypropylene copolymers.

A preferred class of neutral non-cellulosic polymers are comprised ofvinyl copolymers of at least one hydrophilic, hydroxyl-containing repeatunit and at least one hydrophobic, alkyl- or aryl-containing repeatunit. Such neutral vinyl copolymers are termed “amphiphilichydroxyl-functional vinyl copolymers.” Amphiphilic hydroxyl-functionalvinyl copolymers are believed to provide high concentration enhancementsdue to the amphiphilicity of these copolymers which provide bothsufficient hydrophobic groups to interact with the hydrophobic,low-solubility drugs and also sufficient hydrophilic groups to havesufficient aqueous solubility for good dissolution. The copolymericstructure of the amphiphilic hydroxyl-functional vinyl copolymers alsoallows their hydrophilicity and hydrophobicity to be adjusted tomaximize performance with a specific low-solubility drug.

The preferred copolymers have the general structure:

where A and B represent “hydrophilic, hydroxyl-containing” and“hydrophobic” substituents, respectively, and n and m represent theaverage number of hydrophilic vinyl repet units and average number ofhydrophobic vinyl repeat units respectively per polymer molecule.Copolymers may be block copolymers, random copolymers or they may havestructures anywhere between these two extremes. The sum of n and m isgenerally from about 50 to about 20,000 and therefore the polymers havemolecular weights from about 2,500 to about 1,000,000 daltons.

The hydrophilic, hydroxyl-containing repeat units “A” may simply behydroxyl (—OH) or it may be any short-chain, 1 to 6 carbon, alkyl withone or more hydroxyls attached thereto. The hydroxyl-substituted alkylmay be attached to the vinyl backbone via carbon-carbon or etherlinkages. Thus, exemplary “A” structures include, in addition tohydroxyl itself, hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxymethoxy, hydroxyethoxy and hydroxypropoxy.

-   -   The hydrophobic substituent “B” may simply be: hydrogen (—H), in        which case the hydrophobic repeat unit is ethylene; an alkyl or        aryl substituent with up to 12 carbons attached via a        carbon-carbon bond such as methyl, ethyl or phenyl; an alkyl or        aryl substituent with up to 12 carbons attached via an ether        linkage such as methoxy, ethoxy or phenoxy; an alkyl or aryl        substituent with up to 12 carbons attached via an ester linkage        such as acetate, propionate, butyrate or benzoate. The        amphiphilic hydroxyl-functional vinyl copolymers of the present        invention may be synthesized by any conventional method used to        prepare substituted vinyl copolymers. Some substituted vinyl        copolymers such as polyvinyl alcohol/polyvinyl acetate are well        known and commercially available.

A particularly convenient subclass of amphiphilic hydroxyl-functionalvinyl copolymers to synthesize are those where the hydrophobicsubstituent “B” comprises the hydrophilic substituent “A” to which analkylate or arylate group is attached via an ester linkage to one ormore of the hydroxyls of A. Such copolymers may be synthesized by firstforming the homopolymer of the hydrophobic vinyl repeat unit having thesubstituent B, followed by hydrolysis of a portion of the ester groupsto convert a portion of the hydrophobic repeat units to hydrophilic,hydroxyl-containing repeat units having the substituent A. For example,partial hydrolysis of the homopolymer, polyvinylbutyrate, yields thecopolymer, vinylalcohol/vinylbutyrate copolymer for which A is hydroxyl(—OH) and B is butyrate (—OOC—CH₂CH₂CH₃).

For all types of copolymers, the value of n must be sufficiently largerelative to the value of m that the resulting copolymer is at leastpartially water soluble. Although the value of the ratio, n/m variesdepending on the identity of A and B, it is generally at least about 1and more commonly about 2 or more. The ratio n/m can be as high as 200.When the copolymer is formed by hydrolysis of the hydrophobichomopolymer, the relative values of n and m are typically reported in“percent hydrolysis,” which is the fraction (expressed as a percent) ofthe total repeat units of the copolymer that are in the hydrolyzed orhydroxyl form. The percent hydrolysis, H, is given as

$H = {100 \times \left( \frac{n}{n + m} \right)}$

Thus, vinylbutyrate/vinylalcohol copolymer (formed by hydrolysis of aportion of the butyrate groups) having a percent hydrolysis of 75% hasan n/m ratio of 3.

A particularly preferred family of amphiphilic hydroxyl-functional vinylcopolymers are those where A is hydroxyl and B is acetate. Suchcopolymers are termed vinylacetate/vinylalcohol copolymers. Somecommercial grades are also sometimes referred to simply aspolyvinylalcohol. However, the true homopolymer polyvinylalcohol is notamphiphilic and is almost entirely water-insoluble. Preferredvinylacetate/vinylalcohol copolymers are those where H is between about67% and 99.5%, or n/m has a value between about 2 and 200. The preferredaverage molecular weight is between about 2500 and 1,000,000 daltons andmore preferably between about 3000 and about 100,000 daltons.

Another class of polymers suitable for use with the present inventioncomprises ionizable non-cellulosic polymers. Exemplary polymers include:carboxylic acid-functionalized vinyl polymers, such as the carboxylicacid functionalized polymethacrylates and carboxylic acid functionalizedpolyacrylates such as the EUDRAGIT® series manufactured by Rohm TechInc., of Malden, Mass.; amine-functionalized polyacrylates andpolymethacrylates; proteins such as gelatin and albumin; and carboxylicacid functionalized starches such as starch glycolate.

Non-cellulosic polymers that are amphiphilic are copolymers of arelatively hydrophilic and a relatively hydrophobic monomer. Examplesinclude acrylate and methacrylate copolymers. Exemplary commercialgrades of such copolymers include the EUDRAGIT® series, which arecopolymers of methacrylates and acrylates.

A preferred class of polymers comprises ionizable and neutral (ornon-ionizable) cellulosic polymers with at least one ester- and/orether-linked substituent in which the polymer has a degree ofsubstitution of at least 0.05 for each substituent. It should be notedthat in the polymer nomenclature used herein, ether-linked substituentsare recited prior to “cellulose” as the moiety attached to the ethergroup; for example, “ethylbenzoic acid cellulose” has ethoxybenzoic acidsubstituents. Analogously, ester-linked substituents are recited after“cellulose” as the carboxylate; for example, “cellulose phthalate” hasone carboxylic acid of each phthalate moiety ester-linked to the polymerand the other carboxylic acid unreacted.

It should also be noted that a polymer name such as “cellulose acetatephthalate” (CAP) refers to any of the family of cellulosic polymers thathave acetate and phthalate groups attached via ester linkages to asignificant fraction of the cellulosic polymer's hydroxyl groups.Generally, the degree of substitution of each substituent group canrange from 0.05 to 2.9 as long as the other criteria of the polymer aremet. “Degree of substitution” refers to the average number of the threehydroxyls per saccharide repeat unit on the cellulose chain that havebeen substituted. For example, if all of the hydroxyls on the cellulosechain have been phthalate-substituted, the phthalate degree ofsubstitution is 3. Also included within each polymer family type arecellulosic polymers that have additional substituents added inrelatively small amounts that do not substantially alter the performanceof the polymer.

Amphiphilic cellulosics comprise polymers in which the parent cellulosicpolymer has been substituted at any or all of the 3 hydroxyl groupspresent on each saccharide repeat unit with at least one relativelyhydrophobic substituent. Hydrophobic substituents may be essentially anysubstituent that, if substituted to a high enough level or degree ofsubstitution, can render the cellulosic polymer essentiallyaqueous-insoluble. Examples of hydrophobic substitutents includeether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; orester-linked alkyl groups such as acetate, propionate; butyrate, etc.;and ether- and/or ester-linked aryl groups such as phenyl, benzoate, orphenylate. Hydrophilic regions of the polymer can be either thoseportions that are relatively unsubstituted, since the unsubstitutedhydroxyls are themselves relatively hydrophilic, or those regions thatare substituted with hydrophilic substituents. Hydrophilic substituentsinclude ether- or ester-linked nonionizable groups such as the hydroxyalkyl substituents hydroxyethyl, hydroxypropyl, and the alkyl ethergroups such as ethoxyethoxy or methoxyethoxy. Particularly preferredhydrophilic substituents are those that are ether- or ester-linkedionizable groups such as carboxylic acids, thiocarboxylic acids,substituted phenoxy groups, amines, phosphates or sulfonates.

One class of cellulosic polymers comprises neutral polymers, meaningthat the polymers are substantially non ionizable in aqueous solution.Such polymers contain non-ionizable substituents, which may be eitherether-linked or ester-linked. Exemplary ether-linked non-ionizablesubstituents include: alkyl groups, such as methyl, ethyl, propyl,butyl, etc.; hydroxy alkyl groups such as hydroxymethyl, hydroxyethyl,hydroxypropyl, etc.; and aryl groups such as phenyl. Exemplaryester-linked non-ionizable substituents include: alkyl groups, such asacetate, propionate, butyrate, etc.; and aryl groups such as phenylate.However, when aryl groups are included, the polymer may need to includea sufficient amount of a hydrophilic substituent so that the polymer hasat least some water solubility at any physiologically relevant pH offrom 1 to 8.

Exemplary non-ionizable cellulosic polymers that may be used as thepolymer include: hydroxypropyl methyl cellulose acetate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, andhydroxyethyl ethyl cellulose.

A preferred set of neutral cellulosic polymers are those that areamphiphilic. Exemplary polymers include hydroxypropyl methyl celluloseand hydroxypropyl cellulose acetate, where cellulosic repeat units thathave relatively high numbers of methyl or acetate substituents relativeto the unsubstituted hydroxyl or hydroxypropyl substituents constitutehydrophobic regions relative to other repeat units on the polymer.

A preferred class of cellulosic polymers comprises polymers that are atleast partially ionizable at physiologically relevant pH and include atleast one ionizable substituent, which may be either ether-linked orester-linked. Exemplary ether-linked ionizable substituents include:carboxylic acids, such as acetic acid, propionic acid, benzoic acid,salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid orpropoxybenzoic acid, the various isomers of alkoxyphthalic acid such asethoxyphthalic acid and ethoxyisophthalic acid, the various isomers ofalkoxynicotinic acid such as ethoxynicotinic acid, and the variousisomers of picolinic acid such as ethoxypicolinic acid, etc.;thiocarboxylic acids, such as thioacetic acid; substituted phenoxygroups, such as hydroxyphenoxy, etc.; amines, such as aminoethoxy,diethylaminoethoxy, trimethylaminoethoxy, etc.; phosphates, such asphosphate ethoxy; and sulfonates, such as sulphonate ethoxy. Exemplaryester-linked ionizable substituents include: carboxylic acids, such assuccinate, citrate, phthalate, terephthalate, isophthalate,trimellitate, and the various isomers of pyridinedicarboxylic acid,etc.; thiocarboxylic acids, such as thiosuccinate; substituted phenoxygroups, such as amino salicylic acid; amines, such as natural orsynthetic amino acids, such as alanine or phenylalanine; phosphates,such as acetyl phosphate; and sulfonates, such as acetyl sulfonate. Foraromatic-substituted polymers to also have the requisite aqueoussolubility, it is also desirable that sufficient hydrophilic groups suchas hydroxypropyl or carboxylic acid functional groups be attached to thepolymer to render the polymer aqueous soluble at least at pH valueswhere any ionizable groups are ionized. In some cases, the aromaticsubstituent may itself be ionizable, such as phthalate or trimellitatesubstituents.

Exemplary cellulosic polymers that are at least partially ionized atphysiologically relevant pHs include: hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulosesuccinate, hydroxyethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethylcellulose, carboxymethyl cellulose, ethyl carboxymethyl cellulose,cellulose acetate phthalate, carboxymethyl ethyl cellulose, methylcellulose acetate phthalate, ethyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalatesuccinate, hydroxypropyl methyl cellulose acetate succinate phthalate,hydroxypropyl methyl cellulose succinate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate.

Exemplary cellulosic polymers that meet the definition of amphiphilic,having hydrophilic and hydrophobic regions include polymers such ascellulose acetate phthalate and cellulose acetate trimellitate where thecellulosic repeat units that have one or more acetate substituents arehydrophobic relative to those that have no acetate substituents or haveone or more ionized phthalate or trimellitate substituents.

A particularly desirable subset of cellulosic ionizable polymers arethose that possess both a carboxylic acid functional aromaticsubstituent and an alkylate substituent and thus are amphiphilic.Exemplary polymers include cellulose acetate phthalate, methyl celluloseacetate phthalate, ethyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxylpropyl methyl cellulose phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate succinate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate.

Another particularly desirable subset of cellulosic ionizable polymersare those that possess a non-aromatic carboxylate substituent. Exemplarypolymers include hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose succinate, hydroxypropyl celluloseacetate succinate, hydroxyethyl methyl cellulose acetate succinate,hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetatesuccinate and carboxymethyl ethyl cellulose. Of these cellulosicpolymers that are at least partially ionized at physiologically relevantpHs, the inventors have found the following to be most preferred:hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetatetrimellitate and carboxymethyl ethyl cellulose. The most preferred ishydroxypropyl methyl cellulose acetate succinate (HPMCAS).

Another preferred class of polymers consists of neutralized acidicpolymers. By “neutralized acidic polymer” is meant any acidic polymer inwhich a significant fraction of the “acidic moieties” or “acidicsubstituents” have been “neutralized”; that is, exist in theirdeprotonated form. By “neutralized acidic cellulosic polymers” is meantany cellulosic “acidic polymer” for which a significant fraction of the“acidic moieties” or “acidic substituents” have been “neutralized.” By“acidic polymer” is meant any polymer that possesses a significantnumber of acidic moieties. In general, a significant number of acidicmoieties would be greater than or equal to about 0.1 milliequivalents ofacidic moieties per gram of polymer. “Acidic moieties” include anyfunctional groups that are sufficiently acidic that, in contact with ordissolved in water, can at least partially donate a hydrogen cation towater and thus increase the hydrogen-ion concentration. This definitionincludes any functional group or “substituent,” as it is termed when thefunctional group is covalently attached to a polymer, that has a pk_(a)of less than about 10. Exemplary classes of functional groups that areincluded in the above description include carboxylic acids,thiocarboxylic acids, phosphates, phenolic groups, and sulfonates. Suchfunctional groups may make up the primary structure of the polymer suchas for polyacrylic acid, but more generally are covalently attached tothe backbone of the parent polymer and thus are termed “substituents.”Neutralized acidic polymers are described in more detail in commonlyassigned U.S. Patent Application Ser. No. 60/300,255 filed Jun. 22,2001, the relevant disclosure of which is incorporated by reference.

While specific polymers have been discussed as being suitable for use inthe dispersions formable by the present invention, blends of suchpolymers may also be suitable. Thus, the term “concentration-enhancingpolymer” is intended to include blends of polymers in addition to asingle species of polymer.

The amount of concentration-enhancing polymer relative to the amount ofdrug present in the spray-dried dispersions formed by the presentinvention depends on the drug and concentration-enhancing polymer andmay vary widely from a drug-to-polymer weight ratio of 0.01 to 5.However, in most cases, except when the drug dose is quite low, e.g., 25mg or less, it is preferred that the drug-to-polymer ratio is greaterthan 0.05 and less than 2.5 and often the enhancement in drugconcentration or relative bioavailability is observed at drug-to-polymerratios of 1 or less or for some drugs even 0.2 or less. In cases wherethe drug dose is about 25 mg or less, the drug-to-polymer weight ratiomay be significantly less than 0.05. In general, regardless of the dose,enhancements in drug concentration or relative bioavailability increasewith decreasing drug-to-polymer weight ratio. However, due to thepractical limits of keeping the total mass of a tablet, capsule orsuspension low, it is often desirable to use a relatively highdrug-to-polymer ratio as long as satisfactory results are obtained. Themaximum drug:polymer ratio that yields satisfactory results varies fromdrug to drug and is best determined in the in vitro and/or in vivodissolution tests described below.

In general, to maximize the drug concentration or relativebioavailability of the drug, lower drug-to-polymer ratios are preferred.At low drug-to-polymer ratios, there is sufficientconcentration-enhancing polymer available in solution to ensure theinhibition of the precipitation or crystallization of drug from solutionand, thus, the average concentration of drug is much higher. For highdrug/polymer ratios, not enough concentration-enhancing polymer may bepresent in solution and drug precipitation or crystallization may occurmore readily. However, the amount of concentration-enhancing polymerthat can be used in a dosage form is often limited by the maximum totalmass of the dosage form that is acceptable. For example, when oraldosing to a human is desired, at low drug/polymer ratios the total massof drug and polymer may be unacceptably large for delivery of thedesired dose in a single tablet or capsule. Thus, it is often necessaryto use drug/polymer ratios that are less than those which yield maximumdrug concentration or relative bioavailability in specific dosage formsto provide a sufficient drug dose in a dosage form that is small enoughto be easily delivered to a use environment.

Concentration Enhancement

The concentration-enhancing polymer is present in the spray-drieddispersions formed by the present invention in a sufficient amount so asto improve the concentration of the drug in a use environment relativeto a control composition. At a minimum, the compositions formed by thepresent invention provide concentration-enhancement relative to acontrol consisting of undispersed drug alone. Thus, theconcentration-enhancing polymer is present in a sufficient amount sothat when the composition is administered to a use environment, thecomposition provides improved drug concentration relative to a controlconsisting of an equivalent amount of crystalline drug, but with noconcentration-enhancing polymer present.

The compositions formed by the inventive method comprising the drug andconcentration-enhancing polymer provide enhanced concentration of thedissolved drug in in vitro dissolution tests. It has been determinedthat enhanced drug concentration in in vitro dissolution tests in MFDsolution or in PBS solution is a good indicator of in vivo performanceand bioavailability. An appropriate PBS solution is an aqueous solutioncomprising 20 mM Na₂HPO₄, 47 mM KH₂PO₄, 87 mM NaCl, and 0.2 mM KCl,adjusted to pH 6.5 with NaOH. An appropriate MFD solution is the samePBS solution wherein there is also present 7.3 mM sodium taurocholicacid and 1.4 mM of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. Inparticular, a composition formed by the inventive method can bedissolution-tested by adding it to MFD or PBS solution and agitating topromote dissolution. Generally, the amount of composition added to thetest solution is that amount which, if all the drug in the compositiondissolved, would produce a drug concentration that is at least about2-fold and preferably at least about 10-fold the equilibrium solubilityof the drug alone in the test solution. Higher levels of dissolved drugconcentration may be demonstrated by the addition of even larger amountsof the composition.

In one aspect, the compositions formed by the inventive method providean MDC that is at least 1.25-fold the equilibrium concentration of acontrol composition consisting of an equivalent quantity of drug but nopolymer. In other words, if the equilibrium concentration provided bythe control composition is 1 μg/mL, then a composition formed by theinventive method provides an MDC of at least about 1.25 μg/mL. Thecomparison composition is conventionally the undispersed drug alone(e.g., typically, the crystalline drug alone in its mostthermodynamically stable crystalline form, or in cases where acrystalline form of the drug is unknown, the control may be theamorphous drug alone) or the drug plus a weight of inert diluentequivalent to the weight of polymer in the test composition. Preferably,the MDC of drug achieved with the compositions formed by the inventivemethod is at least about 2-fold, more preferably at least about 3-fold,the equilibrium concentration of the control composition.

Alternatively, the compositions formed by the inventive method providein an aqueous use environment an AUC, for any period of from at leastabout 90 minutes to about 270 minutes following introduction to the useenvironment, that is at least about 1.25-fold, preferably at least about2-fold, and most preferably at least about 3-fold, that of a controlcomposition consisting of an equivalent quantity of undispersed drug.

An in vitro test to evaluate enhanced drug concentration in aqueoussolution can be conducted by (1) adding with agitation a sufficientquantity of control composition, typically the drug alone, to the invitro test medium, such as an MFD or a PBS solution, to achieveequilibrium concentration of the drug; (2) adding with agitation asufficient quantity of test composition (e.g., the drug and polymer) inthe same test medium, such that if all the drug dissolved, thetheoretical concentration of drug would exceed the equilibriumconcentration of the drug by a factor of at least 2, and preferably by afactor of at least 10; and (3) comparing the measured MDC and/or aqueousAUC of the test composition in the test medium with the equilibriumconcentration, and/or with the aqueous AUC of the control composition.In conducting such a dissolution test, the amount of test composition orcontrol composition used is an amount such that if all of the drugdissolved the drug concentration would be at least 2-fold and preferablyat least 10-fold that of the equilibrium concentration. Indeed, for someextremely insoluble drugs, in order to identify the MDC achieved it maybe necessary to use an amount of test composition such that if all ofthe drug dissolved, the drug concentration would be 100-fold or evenmore, that of the equilibrium concentration of the drug.

The concentration of dissolved drug is typically measured as a functionof time by sampling the test medium and plotting drug concentration inthe test medium vs. time so that the MDC can be ascertained. The MDC istaken to be the maximum value of dissolved drug measured over theduration of the test. The aqueous AUC is calculated by integrating theconcentration versus time curve over any 90-minute time period betweenthe time of introduction of the composition into the aqueous useenvironment (when time equals zero) and 270 minutes followingintroduction to the use environment (when time equals 270 minutes).Typically, when the composition reaches its MDC rapidly, in say lessthan about 30 minutes, the time interval used to calculate AUC is fromtime equals zero to time equals 90 minutes. However, if the AUC of acomposition over any 90-minute time period described above meets thecriterion of this invention, then the composition formed is consideredto be within the scope of this invention.

To avoid large drug particulates that would give an erroneousdetermination, the test solution is either filtered or centrifuged.“Dissolved drug” is typically taken as that, material that either passesa 0.45 μm syringe filter or, alternatively, the material that remains inthe supernatant following centrifugation. Filtration can be conductedusing a 0.13 mm, 0.45 μm polyvinylidine difluoride syringe filter soldby Scientific Resources of Eatontown, N.J. under the trademark TITAN®.Centrifugation is typically carried out in a polypropylenemicrocentrifuge tube by centrifuging at 13,000 G for 60 seconds. Othersimilar filtration or centrifugation methods can be employed and usefulresults obtained. For example, using other types of microfilters mayyield values somewhat higher or lower (±10-40%) than that obtained withthe filter specified above but will still allow identification ofpreferred dispersions. It should be recognized that this definition of“dissolved drug” encompasses not only monomeric solvated drug moleculesbut also a wide range of species such as polymer/drug assemblies thathave submicron dimensions such as drug aggregates, aggregates ofmixtures of polymer and drug, micelles, polymeric micelles, colloidalparticles or nanocrystals, polymer/drug complexes, and other suchdrug-containing species that are present in the filtrate or supernatantin the specified dissolution test.

Alternatively, the compositions formed by the inventive method, whendosed orally to a human or other animal, provide an AUC in drugconcentration in the blood that is at least about 1.25-fold thatobserved when a control composition consisting of an equivalent quantityof undispersed drug is dosed. It is noted that such compositions canalso be said to have a relative bioavailability of 0.25 about 1.25. Tofacilitate dosing, a dosing vehicle may be used to administer the dose.The dosing vehicle is preferably water, but may also contain materialsfor suspending the test or control composition, provided these materialsdo not dissolve the composition or change the drug solubility in vivo.Preferably, the compositions formed by the inventive method, when dosedorally to a human or other animal, provide an AUC in drug concentrationin the blood that is at least about 2-fold, more preferably at leastabout 3-fold, that observed when a control composition consisting of anequivalent quantity of undispersed drug is dosed. Thus, the compositionsformed by the inventive method can be evaluated in either in vitro or invivo tests, or both.

Relative bioavailability of drugs in the dispersions formed by theinventive method can be tested in vivo in animals or humans usingconventional methods for making such a determination. An in vivo test,such as a crossover study, may be used to determine whether acomposition of drug and concentration-enhancing polymer provides anenhanced relative bioavailability compared with a control compositionconsisting of a drug but no polymer as described above. In an in vivocrossover study a test composition of drug and polymer is dosed to halfa group of test subjects and, after an appropriate washout period (e.g.,one week) the same subjects are dosed with a control composition thatconsists of an equivalent quantity of drug as the test composition butwith no polymer present. The other half of the group is dosed with thecontrol composition first, followed by the test composition. Therelative bioavailability is measured as the concentration in the blood(serum or plasma) versus time area under the curve (AUC) determined forthe test group divided by the AUC in the blood provided by the controlcomposition. Preferably, this test/control ratio is determined for eachsubject, and then the ratios are averaged over all subjects in thestudy. In vivo determinations of AUC can be made by plotting the serumor plasma concentration of drug along the ordinate (y-axis) against timealong the abscissa (x-axis). The determination of AUC is a well-knownprocedure and is described, for example, in Welling, “PharmacokineticsProcesses and Mathematics,” ACS Monograph 185 (1986).

Preparation of Compositions

Dispersions of the drug and concentration-enhancing polymer are made bya spray-drying process, which results in at least a major portion (atleast 60%) of the drug being in the amorphous state. The dispersionsgenerally have their maximum bioavailability and stability when the drugis dispersed in the polymer such that it is substantially amorphous andsubstantially homogeneously distributed throughout the polymer. Ingeneral, as the degree of homogeneity of the dispersion increases, theenhancement in the aqueous concentration of the drug and relativebioavailability increase as well. Thus, most preferred are dispersionshaving a single glass transition temperature, which indicates a highdegree of homogeneity.

In the spray-drying process, the drug and one or moreconcentration-enhancing polymers are dissolved in a common solvent.“Common” here means that the solvent, which can be a mixture ofcompounds, will dissolve both the drug and the polymer(s). After bothdrug and polymer have been dissolved, the solvent is rapidly removed byevaporation in the spray-drying apparatus, resulting in the formation ofa substantially homogeneous, solid amorphous dispersion. In suchdispersions, the drug is dispersed as homogeneously as possiblethroughout the polymer and can be thought of as a solid solution of drugdispersed in the polymer(s), wherein the dispersion is thermodynamicallystable, meaning that the concentration of drug in the polymer is at orbelow its equilibrium value, or it may be considered to be asupersaturated solid solution where the drug concentration in thedispersion polymer(s) is above its equilibrium value.

The solvent is removed by the spray-drying process. The term“spray-drying” is used, conventionally and broadly refers to processesinvolving breaking up liquid mixtures into small droplets (atomization)and rapidly removing solvent from the mixture in a spray-dryingapparatus where there is a strong driving force for evaporation ofsolvent from the droplets. Spray-drying processes and spray-dryingequipment are described generally in Perry's Chemical Engineers'Handbook, pages 20-54 to 20-57 (Sixth Edition 1984). More details onspray-drying processes and equipment are reviewed by Marshall,“Atomization and Spray-Drying,” 50 Chem. Eng. Prog. Monogr. Series 2(1954), and Masters, Spray Drying Handbook (Fourth Edition 1985). Thestrong driving force for solvent evaporation is generally provided bymaintaining the partial pressure of solvent in the spray-dryingapparatus well below the vapor pressure of the solvent at thetemperature of the drying droplets. This is accomplished by (1)maintaining the pressure in the spray-drying apparatus at a partialvacuum (e.g., 0.01 to 0.50 atm); or (2) mixing the liquid droplets witha warm drying gas; or (3) both (1) and (2). In addition, a portion ofthe heat required for evaporation of solvent may be provided by heatingthe spray solution.

Solvents suitable for spray-drying can be any organic compound in whichthe drug and polymer are mutually soluble. Preferably, the solvent isalso volatile with a boiling point of 150° C. or less. In addition; thesolvent should have relatively low toxicity and be removed from thedispersion to a level that is acceptable according to The InternationalCommittee on Harmonization (ICH) guidelines. Removal of solvent to thislevel may require a subsequent processing step such as tray-drying.Preferred solvents include alcohols such as methanol, ethanol,n-propanol, iso-propanol, and butanol; ketones such as acetone, methylethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetateand propylacetate; and various other solvents such as acetonitrile,methylene chloride, toluene, and 1,1,1-trichloroethane. Lower volatilitysolvents such as dimethyl acetamide or dimethylsulfoxide can also beused. Mixtures of solvents, such as 50% methanol and 50% acetone, canalso be used, as can mixtures with water, so long as the polymer anddrug are sufficiently soluble to make the spray-drying processpracticable.

The composition of the solvent-bearing feed will depend on the desiredratio of drug-to-polymer in the dispersion and the solubility of thedrug and polymer in the solvent. Generally, it is desirable to use ashigh a combined drug and polymer concentration in the solvent-bearingfeed as possible, provided the drug and polymer are dissolved in thesolvent, to reduce the total amount of solvent that must be removed toform the solid amorphous dispersion. Thus, the solvent-bearing feed willgenerally have a combined drug and polymer concentration of at leastabout 0.1 wt %, preferably at least about 1 wt % and more preferably atleast about 10 wt %. However, solvent-bearing feeds with lower combineddrug and polymer concentrations can be used to form suitable solidamorphous dispersions.

The solvent-bearing feed, comprising the drug and polymer, is atomizedthrough a pressure nozzle. By “pressure nozzle” is, meant an atomizerthat produces droplets with an average droplet diameter of 50 μm orlarger, with less than about 10 vol % of the droplets having a size lessthan about 10 μm. Generally, an appropriately sized and designedpressure nozzle is one that will produce droplets within this size rangewhen the spray solution is pumped through the nozzle at the desiredrate. Thus, for example, when it is desired to deliver 400 g/min of aspray solution to a PSD-1 dryer, a nozzle must be chosen that is matchedto the viscosity and flow rate of the solution to achieve the desiredaverage droplet size. Too large a nozzle will deliver too large adroplet size when operated at the desired flow rate. This isparticularly true the higher the viscosity of the spray solution.Droplets that are too large result in the rate of drying being too slow,which can yield nonhomogeneous dispersions. Use of a nozzle that is toosmall can yield droplets that are undesirably small or require anunacceptably high pump pressure to achieve the desired flow rate,particularly for high viscosity feed solutions.

A vast majority of atomizers atomize the liquid feed into droplets witha distribution of sizes. The size distribution of droplets produced byan atomizer can be measured by several techniques, including mechanicaltechniques, such as the molten-wax and frozen-drop techniques;electrical techniques, such as charged-wire and hot-wire techniques; andoptical techniques, such as photography and light-scattering techniques.One of the more common methods for determining the droplet sizedistribution produced by an atomizing means is through the use of aMalvern Particle Size Analyzer, available from Malvern Instruments Ltd.of Framingham, Mass. Further details about the principles used, todetermine droplet size and droplet size distribution using suchinstruments can be found in Lefebvre, Atomization and Sprays (1989).

The data obtained using a droplet-size analyzer can be used to determineseveral characteristic diameters of the droplets. One of these is D₁₀,the drop diameter corresponding to the diameter of droplets that make up10% of the total liquid volume containing droplets of equal or smallerdiameter. In other words, if D₁₀ is equal to 10 μm, 10 vol % of thedroplets have a diameter less than or equal to 10 μm. Thus, it ispreferred that the atomizing means produces droplets such that D₁₀ isgreater than about 10 μm, meaning that 90 vol % of the droplets have adiameter of greater than about 10 μm. This requirement ensures thenumber of fines in the solidified product (i.e., particles withdiameters of less than 10 μm) is minimized. Preferably, D₁₀ is greaterthan about 15 μm, more preferably greater than about 20 μm.

Another useful characteristic diameter of the droplets produced by anatomizer is D₉₀, the droplet diameter corresponding to the diameter ofdroplets that make up 90% of the total liquid volume containing dropletsof equal or smaller diameter. In other words, if D₉₀ is equal to 100 μm,90 vol % of the droplets have a diameter less than or equal to 100 μm.For producing substantially homogeneous, substantially amorphousdispersions using the technology of the present invention, the inventorshave found that D₉₀ should be less than about 300 μm, preferably lessthan 250 μm. If D₉₀ is too high, the rate of drying of the largerdroplets may be too slow, which can yield nonhomogeneous dispersions.

Another useful parameter is the “Span,” defined as

${{Span} = \frac{D_{90} - D_{10}}{D_{50}}},$

where D₅₀ is the diameter corresponding to the diameter of droplets thatmake up 50% of the total liquid volume containing droplets of equal orsmaller diameter, and D₉₀ and D₁₀ are defined as above. Span, sometimesreferred to in the art as the Relative Span Factor or RSF, is adimensionless parameter indicative of the uniformity of the drop sizedistribution. Generally, the lower the Span, the more narrow the dropletsize distribution produced by the atomizing means. A narrower dropletsize distribution generally leads to a narrower particle sizedistribution for the dried particles, resulting in improved flowcharacteristics. Preferably, the Span of the droplets produced by thepresent invention is less than about 3, more preferably less than about2, and most preferably less than about 1.5.

The size of the solid dispersion particles formed in the spray-dryer aregenerally somewhat smaller than the size of the droplets produced by theatomizing means. Typically, the characteristic diameter of thedispersion particles is about 80% the characteristic diameter of thedroplets. Thus, in one aspect, the process of the present inventionproduces a solid amorphous dispersion with an average diameter of about40 μm or larger, with less than about 10 vol % of the particles having asize less than about 8 μm. Preferably, at least 80 vol % of thedispersion particles, and more preferably at least 90 vol % havediameters larger than 10 μm. The particles may have a bulk specificvolume of less than 5 mL/g, and preferably less than 4 mL/g. Theparticles may have an average particle size of at least 40 μm,preferably at least 50 μm.

When selecting an atomizer for use in forming a homogeneous solidamorphous dispersion, several factors should be considered, includingthe desired flow rate, the maximum allowable liquid pressure, and theviscosity and surface tension of the solvent-bearing feed. Therelationship between these factors and their influence on droplet sizeand droplet size distribution are well-known in the art.

As noted above, the selection of an atomizer will depend upon the scaleof the spray-drying apparatus used. For smaller scale apparatus,examples of suitable atomizers include the SK and TX spray dry nozzleseries from Spraying Systems, Inc. of Wheaton, Ill.; the WG series fromDelavan LTV of Widnes, Cheshire, England; and the Model 121 nozzle fromDusen Schlick GMBH of Untersiemau, Germany. For larger scale apparatus,exemplary atomizers include the SDX and SDX III nozzles from DelavanLTV.

In many cases the solvent-bearing feed is delivered to the atomizerunder pressure. The liquid pressure required is determined by the designof the pressure nozzle, the size of the nozzle orifice, the viscosityand other characteristics of the solvent-bearing feed, and the desireddroplet size and size distribution. Generally, liquid pressures shouldrange from 2 to 200 atm or more, with 4 to 150 atm being more typical.

The large surface-to-volume ratio of the droplets and the large drivingforce for evaporation of solvent leads to rapid solidification times forthe droplets. Solidification times should be less than about 20 seconds,preferably less than about 10 seconds, and more preferably less than 1second. This rapid solidification is often critical to the particlesmaintaining a uniform, homogeneous dispersion instead of separating intodrug-rich and polymer-rich phases. As noted above, to get largeenhancements in concentration and bioavailability it is often necessaryto obtain as homogeneous a dispersion as possible.

As noted above, the average residence time of particles in the dryingchamber should be at least 10 seconds, preferably at least 20 seconds.However, the actual time the powder remains in the drying chamber istypically longer than the minimum drying time, as calculated above.Typically, following solidification, the powder formed stays in thespray-drying chamber for about 5 to 60 seconds, causing furtherevaporation of solvent. The final solvent content of the soliddispersion as it exits the dryer should be low, since this reduces themobility of drug molecules in the dispersion, thereby improving itsstability. Generally, the solvent content of the dispersion as it leavesthe spray-drying chamber should be less than about 10 wt %, preferablyless than about 3 wt % and most preferably less than about 1 wt %. Asubsequent processing step, such as tray-drying, may be used to removethe solvent to this level.

Excipients and Dosage Forms

Although the key ingredients present in the solid amorphous dispersionare simply the drug and the concentration-enhancing polymer, otherexcipients may be included in the dispersion to improve performance,handling, or processing of the dispersion. Optionally, once formed, thedispersion may be mixed with other excipients in order to formulate thecomposition into tablets, capsules, suppositories, suspensions, powdersfor suspension, creams, transdermal patches, depots, and the like. Thedispersion may be added to other dosage form ingredients in essentiallyany manner that does not substantially alter the drug. The excipientsmay be either separate from the dispersion and/or included within thedispersion.

Generally, excipients such as surfactants, pH modifiers, fillers, matrixmaterials, complexing agents, solubilizers, pigments, lubricants,glidants, flavorants, and so forth may be used for customary purposesand in typical amounts without adversely affecting the properties of thecompositions. See for example, Remington's Pharmaceutical Sciences (18thed. 1990).

One very useful class of excipients is surfactants, preferably presentfrom 0 to 10 wt %. Suitable surfactants include fatty acid and alkylsulfonates; commercial surfactants such as benzalkonium chloride(HYAMINE® 1622, available from Lonza, Inc., Fairlawn, N.J.); dioctylsodium sulfosuccinate (DOCUSATE SODIUM, available from MallinckrodtSpec. Chem., St. Louis, Mo.); polyoxyethylene sorbitan fatty acid esters(TWEEN®, available from ICI Americas Inc., Wilmington, Del.; LIPOSORB®0-20, available from Lipochem Inc., Patterson N.J.; CAPMUL® POE-0,available from Abitec Corp., Janesville, Wis.); and natural surfactantssuch as sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and otherphospholipids and mono- and diglycerides. Such materials canadvantageously be employed to increase the rate of disolution by, forexample, facilitating wetting, or otherwise increase the rate of drugrelease from the dosage form.

The addition of pH modifiers such as acids, bases, or buffers may bebeneficial, retarding the dissolution of the composition (e.g., acidssuch as citric acid or succinic acid when the concentration-enhancingpolymer is anionic) or, alternatively, enhancing the rate of dissolutionof the composition (e.g., bases such as sodium acetate or amines whenthe polymer is cationic).

Conventional matrix materials, complexing agents, solubilizers, fillers,disintegrating agents (disintegrants), or binders may also be added aspart of the composition itself or added by granulation via wet ormechanical or other means. These materials may comprise up, to 90 wt %of the composition.

Examples of matrix materials, fillers, or diluents include lactose,mannitol, xylitol, microcrystalline cellulose, dibasic calcium phosphate(anhydrous and dihydrate) and starch.

Examples of disintegrants include sodium starch glycolate, sodiumalginate, carboxy methyl cellulose sodium, methyl cellulose, andcroscarmellose sodium, and crosslinked forms of polyvinyl pyrrolidonesuch as those sold under the trade name CROSPOVIDONE (available fromBASF Corporation).

Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum and tragacanth.

Examples of lubricants include magnesium stearate, calcium stearate, andstearic acid.

Examples of preservatives include sulfites (an antioxidant),benzalkonium chloride, methyl paraben, propyl paraben, benzyl alcoholand sodium benzoate.

Examples of suspending agents or thickeners include xanthan gum, starch,guar gum, sodium alginate, carboxymethyl cellulose, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyacrylicacid, silica gel, aluminum silicate, magnesium silicate, and titaniumdioxide.

Examples of anticaking agents or fillers include silicon oxide andlactose.

Examples of solubilizers include ethanol, propylene glycol orpolyethylene glycol.

Other conventional excipients may be employed in the compositions ofthis invention, including those excipients well-known in the art.Generally, excipients such as pigments, lubricants, flavorants, and soforth may be used for customary purposes and in typical amounts withoutadversely affecting the properties of the compositions.

Compositions of the present invention may be delivered by a wide varietyof routes, including, but not limited to, oral, nasal, rectal, vaginal,subcutaneous, intravenous, and pulmonary. Generally, the oral route ispreferred.

Compositions of the invention may also be used in a wide variety ofdosage forms for administration of drugs. Exemplary dosage forms arepowders or granules that may be taken orally either dry or reconstitutedby addition of water or other liquids to form a paste, slurry,suspension or solution; tablets; capsules; multiparticulates; and pills.Various additives may be mixed, ground, or granulated with thecompositions of this invention to form a material suitable for the abovedosage forms.

Compositions of the invention may be formulated in various forms so thatthey are delivered as a suspension of particles in a liquid vehicle.Such suspensions may be formulated as a liquid or as a paste at the timeof manufacture, or they may be formulated as a dry powder with a liquid,typically water, added at a later time but prior to oral administration.Such powders that are constituted into a suspension are often referredto as sachets or oral powders for constitution (OPC). Such dosage formscan be formulated and reconstituted via any known procedure. Thesimplest approach is to formulate the dosage form as a dry powder thatis reconstituted by simply adding water and agitating. Alternatively,the dosage form may be formulated as a liquid and a dry powder that arecombined and agitated to form the oral suspension. In yet anotherembodiment, the dosage form can be formulated as two powders that arereconstituted by first adding water to one powder to form a solution towhich the second powder is combined with agitation to form thesuspension.

Generally, it is preferred that the dispersion of drug be formulated forlong-term storage in the dry state as this promotes the chemical andphysical stability of the drug.

Compositions of the present invention may be used to treat any conditionthat is subject to treatment by administering a drug.

Example 1

A solid amorphous dispersion was prepared using a spray-drying apparatusof substantially the same configuration as that shown in FIG. 5. Thedispersion comprised 25 wt % of the low-solubility drug4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (“Drug 1”) and 75 wt % of the amphiphilic polymerhydroxypropyl methyl cellulose acetate succinate (HPMCAS). Drug 1 wasmixed in a solvent (acetone) together with a “medium fine” grade(AQUOT-MF) of HPMCAS (manufactured by Shin Etsu) to form a spraysolution. The spray solution comprised 2.5 wt % Drug 1, 7.5 wt % HPMCAS,and 90 wt % acetone. The spray solution was pumped using a high pressurepump (Z-Drive 2000 High Pressure Gear Pump from Zenith, Inc. of Sanford,N.C.) to a spray-dryer (Niro type XP Portable Spray-Dryer with a LiquidFeed Process Vessel Model No. PSD-1) equipped with a pressure nozzle(Spraying Systems Pressure Nozzle and Body, Model No. SK 71-16). Thedroplet size produced by this pressure nozzle was determined using aMalvern Particle Size Analyzer with the following results: the meandroplet diameter was 125 μm, D₁₀ was 64 μm, D₅₀ was 110 μm and D₉₀ was206 μm, resulting in a Span of 1.3.

The spray-dryer was modified such that the height of the drying chamberwas larger than that supplied with a standard PSD-1 dryer. Thedimensions of the spray-dryer were as follows:

D=0.8 m

H=1.0 m

L=0.8 m.

Thus, the volume of the spray-drying apparatus was

$\begin{matrix}{V_{dryer} = {{\frac{\pi}{4}D^{2}H} + {\frac{\pi}{12}D^{2}L}}} \\{= {{\frac{\pi}{4} \cdot \left( {0.8\mspace{14mu} m} \right)^{2} \cdot \left( {1.0\mspace{14mu} m} \right)} + {\frac{\pi}{12}\left( {0.8\mspace{14mu} m} \right)^{2}\left( {0.8\mspace{14mu} m} \right)}}} \\{= {0.65\mspace{14mu} {m^{3}.}}}\end{matrix}$

The spray-dryer was also equipped with a gas-disperser to produceorganized plug flow of drying gas therethrough. The gas-disperserconsisted of a stainless steel plate with a diameter of 0.8 m thatextended across the top of the drying chamber. The plate had amultiplicity of 1/16-inch (1.7 mm) perforations occupying about 1% ofthe surface area of the plate. The perforations were uniformlydistributed across the plate, except that the density of perforations atthe center 0.2 m of the gas-disperser plate was about 25% of the densityof perforations in the outer part of the plate. The use of the diffuserplate resulted in organized plug flow of drying gas through the dryingchamber and dramatically decreased product recirculation within thespray-dryer. The pressure nozzle sat flush with the gas-disperser plateduring operation.

The spray solution was pumped to the spray-dryer at 180 g/min at apressure of 19 atm (262 psig). Drying gas (nitrogen) was delivered tothe gas-disperser plate at an inlet temperature of 103° C. and a flowrate of 1.6 standard m³/min. The evaporated solvent and drying gasexited the spray drier at a temperature of 51±4° C.

The minimum residence time for the droplets in the spray drier wascalculated as

$\tau = {\frac{0.65}{1.6} = {{0.41\mspace{14mu} \min \times \frac{60\mspace{14mu} \sec}{\min}} = {24\mspace{14mu} {\sec.}}}}$

The spray-dried dispersion formed by this process was collected in acyclone and then dried in a solvent tray dryer by spreading thespray-dried particles onto polyethylene-lined trays to a depth of notmore than 1 cm and then drying them at 40° C. for 16 hours. Afterdrying, the solid dispersion of Example 1 contained 25 wt % Drug 1.Table 1 summarizes the spray-drying conditions used. The overall yieldfor this process was 96%. Inspection of the spray drier after formationof the dispersion showed no evidence of product build-up on thespray-dryer top, the pressure nozzle, the walls of the drying chamber,or on the chamber cone.

Control 1 (C1) consisted of a solid amorphous dispersion of Drug 1 withHPMCAS-MF, spray-dried using a two-fluid spray nozzle (cocurrent,external mix, with a 1.0 mm liquid orifice, Niro Model No. 15698-0100)using the same apparatus. The spray-drying conditions are summarized inTable 1.

TABLE 1 Drug Polymer Solvent Nozzle Feed Ex. Mass Mass Mass PressureRate T_(in) T_(out) Yield No. (g) (g) (g) Nozzle (psig/atm) (g/min) (°C.) (° C.) (%) 1 138 416 4990.5 SK 79-16 262/19 180 103 51 96 C1 24 72855 iro 2-fluid 42/4 190 135 50 85

Samples of Example 1 were analyzed by various methods to determine thephysical properties of the dispersion. First, powder X-ray diffractionanalysis was performed on Example 1 using an AXS D8 Advance from Bruker,Inc. of Madison, Wis. This analysis showed no crystalline peaks in thediffractogram, indicating that the drug in the dispersion was almostcompletely amorphous.

The concentration enhancement provided by the dispersion of Example 1was demonstrated in a dissolution test. For this test, samplescontaining 7.2 mg of Example 1 were added to microcentrifuge tubes, induplicate. The tubes were placed in a 37° C. temperature-controlledchamber, and 1.8 mL PBS at pH 6.5 and 290 mOsm/kg was added. The sampleswere quickly mixed using a vortex mixer for about 60 seconds. Thesamples were centrifuged at 13,000 G at 37° C. for 0.1 minute. Theresulting supernatant solutions were then sampled and diluted 1:6 (byvolume) with methanol and then analyzed by high-performance liquidchromatography (HPLC) at a UV absorbance of 256 nm using a WatersSymmetry C8 column and a mobile phase consisting of 15% (0.2% H3PO4)/85%methanol. The contents of the tubes were mixed on the vortex mixer andallowed to stand undisturbed at 37° C. until the next sample was taken.Collections of the samples were made at 4, 10, 20, 40, 90, and 1200minutes. Control 1 and crystalline Drug 1 were tested using the sameprocedure. The results are shown in Table 2.

TABLE 2 Drug 1 Time Concentration AUC Sample (min) (μg/ml) (min-μg/ml)Example 1 0 0 0 (spray-dried using 4 259 500 pressure nozzle) 10 6713,300 20 704 10,200 40 717 24,400 90 666 59,000 1200 161 518,000 ControlC1 0 0 0 (spray-dried using 4 223 400 two-fluid nozzle) 10 513 2,600 20657 8,500 40 675 21,800 90 711 56,500 1200 387 665,900 Crystalline Drug1 0 0 0 4 <1 <2 10 <1 <8 20 <1 <18 40 <1 <38 90 <1 <88 1200 <1 <1,200

The concentrations of drug obtained in these samples were used todetermine the values of the maximum concentration of drug in the firstninety minutes (C_(max90)) and the area under the curve of drugconcentration versus time in the first ninety minutes (AUC₉₀). Theresults are shown in Table 3. These data show that the dispersion ofExample 1 provided a C_(max90) that was greater than 717-fold that ofthe crystalline control, while the AUC₉₀ was greater than 670-fold thatof the crystalline control. The data also show that the dispersion ofExample 1, made using the pressure nozzle, provided about the sameconcentration enhancement as that of the dispersion of Control 1 madeusing a two-fluid nozzle.

TABLE 3 C_(max90) AUC₉₀ Sample (μg/mL) (min * μg/mL) Example 1 71759,000 Control C1 711 56,500 Crystalline Drug 1 <1 <88

The particle size distribution of the dispersions of Example 1 andControl C1 were determined by light scattering analysis of each drysolid dispersion using an LA-910 Model light-scattering particle sizeanalyzer from Horiba, Inc. of Irvine, Calif. FIG. 6 shows volumefrequency (%) versus particle diameter (μm) for Example 1 and ControlC1. From these data, the mean particle diameter (the peak of the volumefrequency curve) and the percent fines (area under the volume frequencycurve at particle size less than about 10 μm divided by the total areaunder the curve) are summarized in Table 4. These data show that themean diameter of the dispersion particles formed using a pressure nozzleand the spray-dryer design of FIG. 5 (Example 1) were larger than themean diameter of the dispersion particles formed by the same spray-dryerusing a two-fluid nozzle (Control C1). In addition, the number of finesin the dispersion of Example 1 was greatly reduced.

TABLE 4 Mean Particle Particles Having a Diameter Diameter of LessSample (μm) than 10 μm (%) Example 1 53 2.9 Control C1 15 42

The bulk and tapped specific volume of the dispersion of Example 1 wasdetermined using the following procedure. A sample of the dispersion ofExample 1 was poured into a 100-mL graduated cylinder, the tare weightof which had been measured, and the volume and weight of the samplerecorded. The volume divided by the weight yielded the bulk specificvolume of 4.8 mL/g. Next, the cylinder containing the dispersion wastapped 1000 times using a VanKel tap density instrument, Model 50-1200.The tapped volume divided by the same weight of dispersion yielded atapped specific volume of 3.1 mL/g. Similar tests were performed withthe dispersion of Control C1. The results, reported in Table 5, indicatethat the dispersion made with the pressure nozzle (Example 1) had alower specific volume (both bulk and tapped) than the dispersion madeusing a two-fluid nozzle (Control C1). Lower specific volume results inimproved flow characteristics for the dispersion.

TABLE 5 Bulk Tapped Specific Specific Volume Volume Sample (mL/g) (mL/g)Example 1 4.8 3.1 Control C1 5.7 3.3

Comparative Example 1

A solid amorphous dispersion of the same composition as that of Example1 is made using a spray-drying apparatus of substantially the sameconfiguration as that shown in FIG. 4, with a gas-disperser plate of thesame configuration as in Example 1 and having the following dimensions:

D=0.8 m

H=0.8 m

L=0.8 m.

The volume of the spray-drying apparatus is calculated to be 0.53 m³.

When such a spray-dryer is operated under the same conditions as inExample 1, build-up of material on the walls of the drying chamber andcollection cone is predicted, resulting in poor content uniformity andpoor yield.

Example 2

A solid amorphous dispersion was prepared as in Example 1 with the samespray-dryer configuration as in Example 1, except that the height of thedrying chamber H was 2.3 m, resulting in a larger volume for the dryingchamber. Thus, the volume of the spray-drying apparatus was 1.29 m³.Table 6 gives the spray-drying conditions used. Nitrogen drying gas wascirculated through the gas-disperser plate at an inlet temperature of45° C. and a flow rate of 1.4 standard m³/min. The evaporated solventand wet drying gas exited the spray-dryer at a temperature of 10° C.

Referring to Equation I above, the minimum residence time for thedroplets in the spray drier was calculated as

$\tau = {\frac{1.29}{1.4} = {{0.92\mspace{14mu} \min \times \frac{60\mspace{14mu} \sec}{\min}} = {55\mspace{14mu} {\sec.}}}}$

TABLE 6 Drug Polymer Solvent Nozzle Feed Mass Mass Mass Pressure RateT_(in) T_(out) Yield (g) (g) (g) Nozzle (psig/atm) (g/min) (° C.) (° C.)(%) 150 450 5400 SK 80-16 290/21 206 45 10 88

Inspection of the spray-dryer after formation of the dispersion showedno evidence of product build up on the spray-dryer top, the pressurenozzle, the walls of the drying chamber, or on the chamber cone.

The physical properties of the dispersions of Example 2 were determinedas in Example 1. The results are summarized in Table 7, which alsoincludes the results for Example 1, Control C1, and the crystalline Drug1.

TABLE 7 Particles Mean Having a Bulk Tapped Particle Diameter ofSpecific Specific C_(max90) AUC₉₀ Diameter Less Than Volume VolumeSample (μg/mL) (min*μg/mL (μm) 10 μm (%) (mL/g) (mL/g) Example 1 71759,000 70 2.4 4.8 3.1 Example 2 710 55,100 39 4.6 3.6 2.3 Control C1 71156,500 20 17 5.7 3.3 Crystalline <1 <88 — — — — Drug 1

The results show that the dispersion made with the larger volumespray-dryer of Example 2 had similar dissolution properties as thedispersions of Example 1 and Control C1, providing a C_(max90) valuethat was greater than 720-fold that of crystalline Drug 1 alone, and anAUC₉₀ value that was greater than 626-fold that of crystalline Drug 1alone. Furthermore, the mean particle size of the dispersion of Example2 was larger than the dispersion made using the 2-fluid nozzle (ControlC1), and there were significantly fewer fines in the dispersion ofExample 2. The use of the larger volume spray-dryer in Example 2 alsoresulted in a product with a lower specific volume, which yieldedimproved flow characteristics.

Example 3

A solid amorphous dispersion comprising 50 wt % of the low solubilitydrug 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide(“Drug 2”) with HPMCAS-MF was made using the spray-drying apparatus ofExample 1 using a solvent comprising a mixture of 10 wt % water inacetone. The spray-drying conditions are given in Table 8. Nitrogendrying gas was delivered to the gas-disperser plate at an inlettemperature of 103° C. and a flow rate of 1.6 standard m³/min. Theevaporated solvent and drying gas exited the spray drier at atemperature of 51±4° C.

Referring to Equation I above, the minimum residence time for thedroplets in the spray drier was calculated as

$\tau = {\frac{0.65}{1.6} = {{0.41\mspace{14mu} \min \times \frac{60\mspace{14mu} \sec}{\min}} = {24\mspace{14mu} {\sec.}}}}$

Inspection of the spray-dryer after formation of the dispersion showedno evidence of product build-up on the spray-dryer top, the pressurenozzle, the walls of the drying chamber or on the chamber cone.

Control 2 (C2) consisted of a dispersion of Drug 2 with HPMCAS-MF,spray-dried using a Niro two-fluid external-mix spray nozzle using thesame apparatus as in Example 1. Control C2 contained 50 wt % Drug 2. Thespray conditions are noted in Table 8.

TABLE 8 Drug Polymer Solvent Nozzle Feed Ex. Mass Mass Mass PressureRate T_(in) T_(out) Yield No. (g) (g) (g) Nozzle (psig/atm) (g/min) (°C.) (° C.) (%) 3 200 200 2263 SK 80-16 145/11 165 110 44 96 C2 250 2502831 Niro 2-fluid 39/4 39 113 43 85

The physical properties of the dispersions of Example 3, Control C2 andcrystalline Drug 2 alone were determined as Example 1 with the followingexceptions. For concentration enhancement, sufficient quantities of thedispersion were added to the microcentrifuge tubes such that theconcentration obtained if all of the drug had dissolved was 2000 μg/mL.Samples were analyzed by HPLC, with absorbance at 297 nm (HewlettPackard 1100 HPLC, Zorbax SB C18 column, 35% acetonitrile/65% H₂O).

The results of these physical property tests are summarized in Table 9and show that the dispersion made using the pressure nozzle and thespray-dryer design of FIG. 5 (Example 3) had a larger mean particlediameter and fewer fines than the dispersion made using the same dryerdesign with a two-fluid nozzle (Control C2). FIG. 7 shows volumefrequency versus particle diameter for Example 3 (made with a pressurenozzle) and for Control C2. The dissolution performance of thedispersion of Example 3 was slightly better than that of the dispersionmade using a two-fluid nozzle. The dispersion of Example 3 provided aC_(max90) that was 4.9-fold that of the crystalline control, and anAUC₉₀ that was 4.1-fold that of the crystalline control. Finally, theExample 3 dispersion had a lower specific volume than that of ControlC2, yielding a product with improved flow characteristics.

TABLE 9 Particles Mean Having a Bulk Tapped Particle Diameter ofSpecific Specific C_(max90) AUC₉₀ Diameter Less Than Volume VolumeSample (μg/mL) (min*μg/mL (μm ) 10 μm (%) (mL/g) (mL/g) Example 3 73052,200 70 2.4 4.2 3.0 Control C2 580 49,600 20 17 5.0 3.2 Crystalline149 12,800 — — — — Drug 2

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, and there is no intention in the use of such terms andexpressions of excluding equivalents of the features shown and describedor portions thereof, it being recognized that the scope of the inventionis defined and limited only by the claims which follow.

1. A process for producing a pharmaceutical composition comprising thesteps: (a) forming a feed solution comprising a drug, aconcentration-enhancing polymer and a solvent; (b) directing said feedsolution to a spray-drying apparatus comprising (i) a drying chamberhaving a volume V_(dryer) and a height H, (ii) atomizing means foratomizing said feed solution into droplet, (iii) a source of heateddrying gas for drying said droplets, said source delivering said dryinggas to said drying chamber at a flow rate of G, and (iv) gas-dispersingmeans for dispersing said drying gas into said drying chamber, saidgas-dispersing means causing organized plug flow of said drying gas,wherein is measured in m³, H is at least 1 m, G is measured in m³/sec,and wherein the following mathematical relationship is satisfied${\frac{V_{dryer}}{G} \geq {10\mspace{14mu} {seconds}}};$ (c)atomizing said feed solution into droplets in said drying chamber bysaid atomizing means, said droplets having an average diameter of atleast 50 μm and a D₁₀ of at least 10 μm; (d) contacting said dropletswith said heated drying gas to form particulates of a solid amorphousdispersion of said drug and said concentration-enhancing polymer; and(e) collecting said particulates, wherein said concentration-enhancingpolymer is present in said solution in an amount sufficient that saidsolid amorphous dispersion provides concentration enhancement of saiddrug in a use environment relative to a control composition consistingessentially of an equivalent amount of said drug alone.
 2. The processof claim 1 wherein said gas-dispersing means is a perforated plate. 3.The process of claim 2 wherein said perforated plate has perforationsoccupying about 1% of its surface area.
 4. The process of claim 3wherein the density of said perforations near the center of said plateis about 25% the density of said perforations in the outer part of saidplate.
 5. The process of claim 1 wherein said drying gas has an inlettemperature of from about 60° to about 300° C.
 6. The process of claim 5wherein said drying gas has an outlet temperature of from about 0° toabout 100° C.
 7. The process of claim 1 wherein said droplets have a D₁₀of at least 15 μm.
 8. The process of claim 7 wherein said droplets havea D₁₀ of at least 20 μm.
 9. The process of claim 1 wherein said dropletshave a Span of less than about
 3. 10. The process of claim 1 whereinsaid droplets have a Span of less than about
 2. 11. The process of claim1 wherein at least 80 vol % of said particulates have diameters ofgreater than 10 μm.
 12. The process of claim 11 wherein at least 90 vol% of said particulates have diameters of greater than 10 μm.
 13. Theprocess of claim 1 wherein said drug in said dispersion is substantiallyamorphous, and said dispersion is substantially homogeneous.
 14. Theprocess of claim 1 wherein said composition provides a maximum drugconcentration of said drug in said use environment that is at leastabout 1.25-fold that provided by said control composition.
 15. Theprocess of claim 1 wherein said composition provides in said useenvironment an area under the drug concentration versus time curve forany 90-minute period from the time of introduction to about 270 minutesfollowing introduction to said use environment that is at least1.25-fold that provided by said control composition.
 16. The process ofclaim 1 wherein said composition provides a relative bioavailability ofsaid drug that is at least 1.25-fold that of said control composition.17. The process of claim 1 wherein said drug is selected from the groupconsisting of antihypertensives, antianxiety agents, anticlottingagents, anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,anti-atherosclerotic agents, cholesterol-reducing agents, antiobesityagents, autoimmune disorder agents, anti-impotence agents, antibacterialand antifungal agents, hypnotic agents, anti-Parkinsonism agents,anti-Alzheimer's disease agents, antibiotics, anti-depressants,antiviral agents, glycogen phosphorylase inhibitors, and cholesterolester transfer protein inhibitors.
 18. The process of claim 17 whereinsaid drug is selected from the group consisting of[R-(R*S*)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide;[2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; and[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.
 19. The process of claim 1 wherein saidconcentration-enhancing polymer, is selected from the group consistingof ionizable cellulosic polymers, non-ionizable cellulosic polymers,ionizable non-cellulosic polymers, non-ionizable non-cellulosicpolymers, neutralized acidic polymers and blends thereof.
 20. Theprocess of claim 19 wherein said polymer is selected from the groupconsisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose,carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose phthalate, cellulose acetatephthalate, cellulose acetate trimellitate, polyvinyl alcohols that haveat least a portion of their repeat units in hydrolyzed form, polyvinylpyrrolidone, poloxamers and blends thereof.